PROJECT SUMMARY
This proposed study will comprehensively stage individual disease burden and mortality risk
at initial diagnosis and across the course of care for patients with chronic limb threatening
ischemia (CLTI). This debilitating, progressive condition is the most severe form of peripheral
artery disease, and successful treatment requires ongoing combinations of endovascular or
open revascularization, medical and wound/podiatric care. Because CLTI manifests in the
extremities, limb-based classification systems like the existing Wound, Ischemia, and foot
Infection (WIfI) staging system are important tools; however, the goals for CLTI treatment are
often broader than limb salvage and include freedom from recurrent disease and survival.
Despite the availability of multiple life- and limb-preserving treatments, success in improving
health outcomes of patients afflicted with CLTI has been limited. The recently completed BEST-
CLI randomized controlled trial with 1830 adult participants determined that surgical vein bypass
is the most effective initial revascularization approach for patients with CLTI, but almost 10%
required re-intervention to maintain blood flow to the limb, 10% underwent major limb
amputation, and 33% died within two years. The need for frequent re-intervention for patients in
the BEST-CLI study demonstrates that long-term CLTI and survival outcomes are dependent on
the sequence of treatments beyond the initial revascularization strategy. Yet, how post-primary
revascularization treatment impacts outcomes among different types of patients is unknown.
Our proposed study addresses these limitations. Using precision medicine analytics and
machine learning, we will leverage the rich BEST-CLI trial data to identify clusters of limb
characteristics, anatomic patterns of atherosclerosis, and comorbidities that associate with
differing levels of CLTI-free survival. Moreover, with the BEST-CLI longitudinal patient
assessments, we will quantify the impact of different post-primary revascularization treatments
on CLTI-free survival. This study will provide a deeper understanding of the limb- and life-
preserving effect of different combinations of medical and surgical treatments over time,
especially among patients who do not respond to first-line surgical interventions. Together, our
results will help clinicians set expectations and, if warranted, change practice based on likely
CLTI-free survival at initial diagnosis and over the lifespan of each patient. In the future, the
evidence generated from our study will be incorporated into precision medicine clinical trials
such sequential multiple assignment randomized trials (SMARTs) for discovering and testing
optimal, individually tailored treatment regimens for CLTI.
